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Abstract:

A paliperidone double-layered osmotic pump controlled release tablet and
the preparation method thereof are disclosed. The double-layered osmotic
pump controlled release tablet comprises a rigid membrane, a push layer,
a drug layer, an isolation layer and an aesthetic coating, wherein the
rigid membrane contains a semi-permeable polymer, a porogen and/or a
plasticizer and has one or more drug release orifices on one end, the
push layer comprises an expanding material, an osmotic agent, a binder, a
colorant and a lubricant, the drug layer contains a pharmaceutically
active ingredient, a hydrophilic polymer, an osmotic agent, a colorant, a
lubricant and an antistatic agent, the isolation layer is located between
the inner surface of the rigid membrane and the push layer, and contains
a hydrophilic polymer. The paliperidone double-layered osmotic pump
controlled release tablet shows an increasing drug release rate at early
stage and keeps a constant drug release rate at later stage.

Claims:

1. A paliperidone double layered osmotic pump controlled release tablet
comprising: a moisture-permeable rigid membrane shell having one or more
drug release orifices at one end thereof, which is made of the controlled
release layer composition comprising a semi-permeable polymer, a porogen
and/or a plasticizer; a push layer inside the rigid membrane shell and
away from the side of the drug release orifice, which is made of a push
layer composition comprising an expansion material, an osmotic agent, a
binder, and optionally, a colorant and a lubricant; a drug layer inside
the rigid membrane shell, adjacent to the release orifices and directly
contacting with the push layer, which is made of a drug layer composition
comprising a pharmaceutically active ingredient, one or more kinds of
hydrophilic polymer carriers, and optionally, an osmotic agent, a
colorant, a lubricant and an antistatic agent; an isolation layer located
between the inside surfaces of the rigid membrane shell and the tablet
core consisting of the drug layer and the push layer, which is made of an
isolation layer composition comprising 0.about.30%, preferably 0.1 to 15%
of a pharmaceutically active ingredient based on the total weight of the
isolation layer composition, and the others are one or more hydrophilic
polymers; an optional aesthetic coating layer coated on the outer surface
of the rigid membrane shell, which is made of an aesthetic coating layer
composition comprising coating powder for forming the aesthetic coating,
and optionally, one or more excipients selected from the group consisting
of colorant, a plasticizer, an opacifying agent, and an anti-sticking
agent; wherein the hydrophilic polymer carrier in the drug layer is
selected from the group consisting of povidone, copolymerized povidone,
carbomer, hydroxypropyl cellulose, hypromellose and mixtures thereof;
wherein the said paliperidone double layered osmotic pump controlled
release tablet shows an gradually increasing release rate at early stage
and maintains a constant release rate at later stage.

2. The paliperidone double layered osmotic pump controlled release tablet
according to claim 1, wherein the proportion of the hydrophilic polymer
carriers in the drug layer composition is 65 to 99%, preferably 70 to 95%
based on total weight of the drug layer composition.

3. The paliperidone double layered osmotic pump controlled release tablet
according to claim 1, wherein the duration of the early stage with the
gradually increasing release rate is at least 3 hours, preferably 5
hours, and the duration of the later stage maintaining the constant
release rate is at least 5 hours, preferably 6 to 12 hours.

5. The paliperidone double layered osmotic pump controlled release tablet
according to claim 1, wherein the pharmaceutically active ingredient is
selected from the group consisting of paliperidone, the pharmaceutically
acceptable salts or esters thereof.

6. The paliperidone double layered osmotic pump controlled release tablet
according to claim 1, wherein the pharmaceutically active ingredient
takes up 0.1 to 25 wt %, preferably 1 to 20 wt % in the drug layer
composition, based on the total weight of the drug layer.

7. The paliperidone double layered osmotic pump controlled release tablet
according to claim 1, wherein the pharmaceutically active ingredient
takes up 0 to 30 wt %, preferably 0.1 to 15 wt % in the isolation layer
composition based on the total weight of the isolation layer composition.

9. The paliperidone double layered osmotic pump controlled release tablet
according to claim 1, wherein, based on the total weight of the drug
layer, the antistatic agent takes up 0 to 8 wt % in the drug layer.

15. The paliperidone double layered osmotic pump controlled release
tablet according to claim 1, wherein the binder in the push layer is
selected from the group consisting of povidone, copolymerized povidone,
hypromellose and mixtures thereof.

17. A method for preparing the paliperidone double layered osmotic pump
controlled release tablet according to claim 1, comprising the steps of:
(1) uniformly mixing the various components of the drug layer composition
in formulated amounts, and then preparing granules of the drug layer
composition; (2) uniformly mixing the various components of the push
layer composition in formulated amounts, and then preparing granules of
the push layer composition; (3) pressing the above prepared granules of
the drug layer composition and the push layer compositionin formulated
amounts into double-layered tablet core; (4) coating the above
double-layered tablet core with the isolation layer composition; (5)
coating the double-layered tablet core coated with the isolation layer
composition by using the controlled release layer composition; (6)
perforating a drug-release orifice on the coated tablet obtained in step
(5); (7) optionally, coating the controlled release tablet obtained in
step (6) with the aesthetic coating layer composition.

Description:

FIELD OF THE INVENTION

[0001] The present invention relates to a controlled release dosage form
of a benzoisoxazole derivative, and more particularly, to a paliperidone
double-layered osmotic pump controlled release tablet and preparation
method thereof. The paliperidone double-layered osmotic pump controlled
release tablet may be used for the treatment of schizophrenia and bipolar
mania.

BACKGROUND OF THE INVENTION

[0002] Schizophrenia, which is characterized by the change of basic
personality, the schism of thinking, feeling and behavior, and the
disharmony of psychomotility and surroundings, is a most common type of
mental illness and belongs to the severe type. Schizophrenia mainly
occurs in young and middle-aged people without organic change, and it is
a functional psychosis. Patients suffering from schizophrenia generally
have no impediment in consciousness and intelligence, but when there is
schizophrenic attack, it not only affects the labor capacity of the
patients, but also exerts great influence on working, studying, living
and socializing of the patients themselves. Medication therapy is one of
the most commonly-used and effective treatment methods so far, and it can
not only effectively control the schizophrenic symptoms, but also
significantly control and reduce the frequency and intensity of the onset
of the disease.

[0003] Antipsychotics are usually classified into two categories of
typical and atypical according to the mechanism of action: (1) typical
antipsychotics (traditional antipsychotics), whose representatives
include chloropromazine, haloperidol and the like; (2) atypical
antipsychotics (nontraditional antipsychotics), whose representatives
include paliperidone, clozapine, risperidone and the like. Compared with
the traditional medicines, the atypical antipsychotics have lower
affinity with dopaminergic D2 receptor, but have higher affinity with
5-hydroxytryptamine and noradrenergic receptor. Meanwhile, atypical
antipsychotics have broad treatment spectrum and significant effect on
negative symptoms when compared to traditional medicines, and they have
high security, fewer adverse effect and low dosage, significantly
improving the compliance of the patients.

[0004] Paliperidone (9-hydroxyrisperidone), which is a benzoisoxazole
derivative, is a new type of antipsychotic, and the exact mechanism of
action thereof is still unclear. It is now thought that paliperidone
blocks the signal transmission of neurotransmitters in brain of the
patients by blocking dopaminergic (D), 5-hydroxytryptamine-2A (5HT2) and
adrenergic receptors. Paliperidone has an oral bioavailability of 28%, a
plasma protein binding rate of 74%, a half-life of the terminal
elimination phase of about 23 h, and an apparent volume of distribution
of 487 L. The major adverse effects after oral administration of
paliperidone include anxiety, somnolence, dizziness, constipation,
extrapyramidal symptoms and the like.

[0006] Chinese patent publication No. CN101,264,084 provides a method for
the treatment of psychiatric patients having or at risk of hepatic
impairment, which comprises administering a therapeutically effective
dose of paliperidone, its pharmaceutically acceptable acid addition
salts, enantiomer and esters thereof to psychiatric patients in need
thereof.

[0007] In the international application Nos. WO 00/35419, WO 96/31201, WO
01/34120 and U.S. Pat. Nos. 5,654,008; 5,650,173; 5,770,231; 6,077,843;
6,368,632; 6,110,923; 5,695,168; 5,692,477; 5,871,778; 5,656,299,
paliperidone is used as the model drug to prepare various dosage forms
such as liquid gelatin capsule, transdermal patch, long-acting injection
implant and the like, but the preparation of osmotic pump controlled
release tablet using paliperidone is not disclosed.

[0008] Osmotic pump controlled release tablet is an oral controlled
release drug delivery system based on osmosis, which is a general
technology for the preparation of sustained/controlled release dosage
form. U.S. Pat. Nos. 3,845,770; 3,916,899; 3,995,631; 4,008,719;
4,160,020; 4,034,758; 4,327,725; 4,578,075; 4,681,583; 4,783,337;
5019397; 5,156,850 describe the osmotic pump controlled release
technology in detail, which are incorporated herein by reference. Osmotic
pump controlled release dosage form usually has the following advantages:
(1) it possesses a preset drug-release kinetic behavior; (2) it is less
influenced by the factors such as pH of the medium, gastrointestinal
peristalsis and food; and has a good relevance between in vivo and in
vitro; (3) it is capable of avoiding the phenomenon of large fluctuation
range of blood concentration caused by common oral dosage forms; (4) it
is capable of reducing the frequency of administration, and improving the
compliance of patients.

[0009] On the basis of above advantages of the osmotic pump controlled
release tablet, paliperidone may be combined with the osmotic pump
controlled release drug delivery system to prepare paliperidone osmotic
pump controlled release tablet, as a preferred oral osmotic(OROS) dosage
form, so as to further reduce the neural adverse reactions (mainly
extrapyramidal symptoms) of atypical antipsychotics, to decrease the
fluctuation of blood concentration, to increase therapeutic effect, and
to improve the compliance of patients.

[0010] At present, a commercially available paliperidone sustained release
tablet (trade name: Invega) is a benzoisoxazole antipsychotic developed
by Janssen L P, a member of Johnson & Johnson, US, and it was approved by
FDA for marketing on Nov. 29, 2005, which was indicated for the treatment
of schizophrenia and bipolar mania.

[0011] Chinese patent publication No. CN1,684,670A discloses a dosage form
of substantially releasing paliperidone and preparation method thereof.
The sustained release dosage form provides a therapeutically effective
plasma concentration of paliperidone when administered once daily. The
capsule-shaped sustained release tablet containing paliperidone of the
invention is orally administered to release paliperidone at a
substantially ascending release rate during the prolonged period of time.
This invention describes in detail the preparation method of paliperidone
capsule-shaped osmotic pump controlled release tablet, the main excipient
of the tablet core is a polymeric material--polyoxyethylene.
Unfortunately, however, we have found that the three-layered capsule
shaped osmotic pump controlled release tablet still has some
disadvantages for the following reasons, for example:

[0012] (1) It needs a special preparation process with a high production
cost. The preparation process of the three-layered osmotic pump
controlled release tablet is comparatively complicated, wherein it
requires to prepare two kinds of drug layer particles with different drug
contents and determined respectively the drug content, and then press
into tablet, and thus the preparing period is long with more workload.
The common used doses of paliperidone include 3 mg, 6 mg, and 9 mg, which
belong to the low dose drug, and thus paliperidone has high requirements
for content uniformity of the tablet core. But for a three-layered
tablet, it is more difficult to achieve a satisfactory content uniformity
Therefore, the preparation of a three-layer capsule shaped osmotic pump
controlled release tablet requires a specific tablet compressor
(three-layered tablet press), with a higher machining precision.

[0013] (2) The main excipient for tablet core has a poor thermal
stability. Polyoxyethylene is a kind of high molecular polymer with poor
thermal stability and which has low glass transition temperature
(62˜67° C.). Due to the above features, it has the following
problems during the industrial production and storage. (i) It is
difficult to dry off the solvent during granulation process. The drying
temperature for polyoxyethylene is generally less than 40° C.,
thus easily leading to problems of insufficient dryness and high residue
of organic solvent; and if a complete dryness is required, it requires a
relatively long drying duration, which results in higher production cost.
(ii) The storage temperature of the tablet should not be too high, and
the tablet has to be stored in a cool, dark place, which increases the
storage cost. Meanwhile, a high storage temperature tends to cause some
changes in the physicochemical properties of polyoxyethylene, such as,
the oxidative degradation of polyoxyethylene, the decrease in the
viscosity of the tablet core, which eventually result in the acceleration
of the release of the controlled release tablet, and this will increase
potentially dangerous factors to the treatment of patients. (iii) During
high-speed tablet pressing, the punch die repeatedly rubs to generate
heat, and when the temperature reaches about 50° C., phenomena
such as sticking, rough appearance of tablet core, rolled edge in part of
the tablet core would likely appear. Therefore, it usually requires a
special cooling equipment to control the temperature of punch die. For
the osmotic pump controlled release tablet, the rolled edge in part of
the tablet core is likely to cause vulnerable point in the coating
membrane in the said part, which may lead to the fracture of the coating
membrane in the course of release. Consequently, it affects the release
rate of the drug, and more seriously, a sudden release of the drug caused
by the fracture of the coating membrane may directly contribute to the
fluctuation of blood concentration, thus increase the potential risk and
adverse reaction of the administration of the psychotic patients, which
goes against the purpose for preparing osmotic pump controlled release
tablet.

[0014] (3) The three-layered capsule shaped osmotic pump controlled
release system releases paliperidone at a substantially ascending release
rate, which results in a relatively large fluctuation range of blood
concentration, and thus reduces the safety, effectiveness and compliance
of the administration.

[0015] Therefore, there is a need to provide a paliperidone osmotic pump
controlled release tablet, which has a simple preparation process, low
cost excipients for tablet core and good thermal stability, and is
capable of effectively control the release rate of the drug to keep the
curve of blood concentration smooth and reduce its fluctuation, and thus
improve safety, effectiveness and compliance of the administration.

DETAILED DESCRIPTION OF THE INVENTION

Technical Problems

[0016] To solve the above problems, one object of the present invention is
to provide an double layered osmotic pump controlled release tablet
comprising a benzoisoxazole derivative, specifically, a paliperidone
double layered osmotic pump controlled release tablet, which shows an
increasing release rate in early stage and maintaining a constant release
rate in the later stage. The paliperidone double layered osmotic pump
controlled release tablet has advantages of simple preparation process,
low cost excipients for the tablet core, and good thermal stability etc.,
and has an improved drug release curve, a release rate free of the
influence of gastrointestinal peristalsis and pH value, a small
individual difference, a stable plasma concentration, and a long-term
therapeutic effectiveness, eliminating the peak-trough phenomenon and
reducing adverse reactions, and thereby increasing the safety, efficacy
and compliance of the administration. The paliperidone double layered
osmotic pump release tablet according to the present invention can be
used for the treatment of schizophrenia and bipolar mania.

[0017] Another object of the present invention is to provide a method for
preparation of the above paliperidone double layered osmotic pump release
tablet.

Technical Solutions

[0018] To achieve the above objects, the present invention Provides a
paliperidone double layered osmotic pump release tablet showing an
increasing release rate in early stage and maintaining a constant release
rate in later stage, which comprises:

[0019] a moisture-permeable rigid membrane shell having one or more
drug-release orifices at one end thereof, which is made of a controlled
release layer composition comprising a semi-permeable polymer, as well as
a porogen and /or a plasticizer;

[0020] a push layer inside the rigid membrane shell and away from the side
of the release orifices, which is made of a push layer composition
comprising a expansion material, an osmotic agent, a binder, and
optionally, a colorant and a lubricant;

[0021] a drug layer inside the rigid membrane shell, adjacent to the
release orifices and directly contacting with the push layer, which is
made of a drug layer composition comprising a pharmaceutically active
ingredient, one or more kinds of hydrophilic polymer carriers, and
optionally, a osmotic agent, a colorant, a lubricant and an antistatic
agent, based on total weight of the drug layer composition;

[0022] an isolation layer located between the inside surface of the rigid
membrane shell and a tablet core consisting of the drug layer and the
push layer, which is made of an isolation layer composition comprising
one or more hydrophilic polymers and optionally, a pharmaceutically
active ingredient, based on the total weight of the isolation layer
composition;

[0023] an optional aesthetic coating layer coating on the outer surface of
the rigid membrane shell, which is made of an aesthetic coating layer
composition comprising coating powder for forming the aesthetic coating,
and optionally, one or more excipients selected from the group consisting
of a colorant, a plasticizer, a opacifying agent, an anti-sticking agent
and the like;

[0024] wherein the hydrophilic polymer carrier in the drug layer is
selected from the group consisting of povidone, copolymerized povidone,
carbomer, hydroxypropyl cellulose, hypromellose and mixtures thereof.

[0025] The present invention use a mature process technique with high
machining precision to prepare the paliperidone double layered osmotic
pump release tablet, which will facilitate the manufacturers to greatly
simplify the production process and reduce production costs. At the same
time, in order to solve the problem of the thermal stability of the
excipients in the tablet core of the three-layered osmotic pump release
tablet described in Chinese patent application No. CN 1,684,670 A, the
inventors screened and designed a novel drug layer composition and a
novel push layer composition, and prepared the paliperidone double
layered osmotic pump release tablet in company with an isolation layer
composition. The new designed tablet core has a good thermal stability
with a high glass transition temperature, therefore solving the drying
problems, sticking problems in the high-speed tablet-pressing and the
storage problems of the excipients and tablet. Additionally, the new
designed formulation is well compressible and suitable for high-speed
tablet-pressing, and the preparation process thereof is mature, stable
and reproducible. On the other hand, the excipients used in the novel
formulation is non-toxic, has no irritation for skin, no allergic
reactions, and will not be absorbed by gastrointestinal tract, and mucosa
after oral administration. Therefore, the effect of the factors such as
gastrointestinal peristalsis, pH, food and the like on the drug release
can be avoided. At the same time, the specific designed double layered
osmotic pump release tablet can show a increasing release rate at the
initial stage, and it will release the drug at a constant release rate
after plasma concentration reaching an effective concentration. This
release behavior can not only ensure that the plasma concentration able
to rapidly achieve the therapeutically effective concentration in the
early stage, but also guarantee a more stable plasma concentration curve
in the later stage of the drug release and reduce the fluctuation of
plasma concentration, thereby greatly improves the safety, efficacy and
compliance of the administration.

[0026] The paliperidone double layered osmotic pump controlled release
tablet according to the present invention can provide at least 3 hours,
preferably 5 hours of an early stage with the increasing drug-release
rate, and at least 5 hours, preferably 6 to 12 hours of a later stage at
a constant drug-release rate. The designed drug-release behavior can
ensure a rapid release at the early stage to reach the therapeutic
concentration in order to achieve a rapid onset, and also guarantee a
relative constant plasma concentration by the constant release rate in
the later stage.

[0027] The term of "increasing release rate" in the present invention
means that the release rate of the active substance from the membrane
shell in a certain period increases with the time measured by a release
determination method. The term of "constant release rate" in the present
invention means that release rate of the active substance from the
membrane shell is basically constant in a certain period measured by a
release determination method, and the relative standard deviation thereof
does not exceed 25%.

[0028] In the paliperidone double layered osmotic pump controlled release
tablet according to the present invention, based on the total weight of
the controlled release tablet, the weight percentages of various layers
are as follows: the drug layer takes up 10 to 80 wt %, preferably 20 to
70 wt %, more preferably 30 to 70 wt %, and most preferably 30 to 60 wt
%; the push layer takes up 15 to 60 wt %, preferably 20 to 55 wt %, more
preferably 20 to 50 wt %, and most preferably 25 to 50 wt %; the
isolation layer takes up 0.1 to 30 wt %, preferably 2 to 30 wt %, more
preferably 5 to 25 wt %, and most preferably 10 to 25 wt %; the membrane
shell takes up 0.1 to 15 wt %, preferably 0.5 to 12 wt %, more preferably
2 to 10 wt %, and most preferably 4 to 10 wt %; the aesthetic coating
layer takes up 0 to 20 wt %, preferably 0.1 to 15 wt %, more preferably 1
to 10 wt %, and most preferably 2 to 8 wt %.

[0029] The drug layer according to the present invention is made of a drug
layer composition comprising a pharmaceutically active ingredient, one or
more kinds of hydrophilic polymer carriers and, optionally, excipients
such as an antistatic agent, an osmotic agent, a lubricant, a colorant,
etc.

[0030] The pharmaceutically active ingredient is selected from the group
consisting of paliperidone, the pharmaceutically acceptable salts or
esters thereof. Based on the total weight of the drug layer composition,
the active ingredient takes up 0.1 to 25 wt %, preferably 1 to 20 wt %,
more preferably 2 to 15 wt % in the drug layer composition.

[0031] The hydrophilic polymer carrier can provide a uniform and
controlled release rate of the pharmaceutically active ingredient for the
paliperidone double layered osmotic pump controlled release tablet
according to the present invention, and is selected from the group
consisting of povidone, copolymerized povidone, carbomer, hydroxypropyl
cellulose, hypromellose and mixtures thereof. These hydrophilic polymer
carriers have relatively low price, are physiological inert materials
with a high oral safety, and are also thermal stable and have high glass
transition temperature so as to solve the problem of thermal stability of
the excipients in tablet core. The proportion of the hydrophilic polymer
carrier in the drug layer composition is 65 to 99%, preferably 70 to 95%
based on the total weight of the drug layer composition.

[0032] The inventors, during the preparation, unexpectedly found that
there is a strong electrostatic effect between the active ingredient
paliperidone and excipients in the mixing process so that the active
ingredient is easily adhered to the inner wall of the container,
resulting in poor content uniformity of the materials. In order to
prevent the unqualified content uniformity due to the uneven mixing of
the materials, an antistatic agent is added into the formulation of the
drug layer. The antistatic agent includes one or more selected from the
group consisting of silicon dioxide, stearic acid, and polyethylene
glycol, preferably is silicon dioxide. Based on the total weight of the
drug layer, the antistatic agent takes up 0 to 8 wt %, preferably 0.1 to
5 wt %, more preferably 0.1 to 2 wt % in the drug layer.

[0033] The present invention is an oral controlled-release drug delivery
system based on permeation. The use of an osmotic agent can facilitate
the hydration rate of the tablet core of drug layer. The osmotic agent is
selected from the group consisting of sodium chloride, lactose, mannitol,
sorbitol, glucose, sucrose, fructose and mixture thereof, preferably is
sodium chloride, or lactose. The osmotic agent takes up 0 to 30 wt % in
the drug layer composition based on the total weight of the drug layer
composition.

[0034] Since the content of the pharmaceutically active ingredient is low
in the paliperidone double layered osmotic pump controlled release tablet
according to the present invention, the addition of a lubricant can
improve the granules' flowability for the drug layer and push layer
during the high-speed tablet-pressing and ultimately improve the labeled
amount and content uniformity of the final product. The used lubricant
should be inert to the pharmaceutically active ingredients of the present
dosage form, and it is selected from the group consisting of the
following known materials for the skilled person in the art, such as
stearic acid, magnesium stearate, sodium stearylfumarate, talc, waxes,
and their mixtures. The lubricant takes up 0 to 3%, preferably 0.5 to 2%
in the drug layer, based on the total weight of the drug layer
composition.

[0035] The use of a colorant can facilitate to identify the drug layer and
the push layer. However, the color of the drug layer and the push layer
is inconsequential, and color selection does not influence the usage and
effect of the present invention. The colorants can be one or more
selected from the group consisting of iron oxide red, iron oxide yellow,
iron oxide purple, iron oxide black and mixture thereof. The colorant
takes up 0 to 2%, preferably 0.1 to 1%, in the drug layer composition,
based on the total weight of the drug layer composition.

[0036] The push layer is a high molecular material layer with
self-expandable and promoting effects. It is adjacent to the drug layer,
and made of a push layer composition. The push layer composition usually
comprises pharmaceutical excipients such as an expansion material, an
osmotic agent, a binder, and optionally, a colorant and a lubricant etc.

[0037] The expansion material is generally a high molecular polymer, which
will swell after absorbing water in an aqueous media so as to push the
release of drug from the drug layer composition. The expansion material
is selected from the group consisting of the following known materials
for a skilled person in the art, such as sodium carboxymethyl starch, low
substituted hypromellose, hypromellose, hydroxypropyl cellulose,
croscarmellose sodium, crospovidone, carbomer and mixture thereof, and
preferably a mixture of sodium carboxymethyl starch, carbomer and
hypromellose. The expansion material takes up 20 to 80%, preferably 30 to
75%, more preferably 30 to 60% in the push layer composition, based on
the total weight of the push layer composition.

[0038] The effect and selectable categories of the osmotic agent used in
the push layer composition are same as that used in the drug layer
composition. The osmotic agent in the push layer composition takes up 10
to 45%, preferably 20 to 35% based on the total weight of the push layer
composition.

[0039] The binder is generally selected from the group consisting of
povidone, copolymerized povidone, hypromellose and mixture thereof. The
binder in the push layer composition takes up 0 to 30%, preferably 10 to
30% based on the total weight of the push layer composition.

[0040] The effect and selectable categories of the lubricant used in the
push layer composition are same as that used in the drug layer
composition. The lubricant in the push layer composition takes up 0 to
3%, preferably 0.1 to 1.5% based on the total weight of the push layer
composition.

[0041] The effect and selectable categories of the colorant used in the
push layer composition are same as that used in the drug layer
composition. The colorant in the push layer composition takes up 0 to 2%,
preferably 0.1 to 1% based on the total weight of the push layer
composition.

[0042] The above drug layer and push layer constitute the tablet core of
the paliperidone double layered osmotic pump release tablet according to
the present invention. The method for preparing the double layered tablet
is the common option for the skilled person in the art, for example, a
single punch tablet press or double-layer tablet press can be applied to
produce the tablet core of the paliperidone double layered osmotic pump
release tablet according to the present invention.

[0043] The isolation layer is used to provide protection for the tablet
core of the paliperidone double layered osmotic pump release tablet
according to the present invention. It is a novel combination to combine
the main excipients of the tablet core and the pharmaceutically active
ingredient of the present dosage form in company with the isolation
layer. The paliperidone double layered osmotic pump release tablet
prepared by this combination is characterized by significantly controlled
release, so that the safety of the drug can be further improved.

[0044] The isolation layer may be formed through dissolving the isolation
layer composition in a proper solvent to prepare an isolation layer
coating solution, and then spray-coated on the tablet core and drying, or
may be made by tablet press. Preferably, the isolation layer is made by
the tablet coating. The isolation layer composition consists of a
hydrophilic material, which is selected from the group consisting of the
following known materials for a person skilled in the art, such as
hypromellose, povidone, copolymerized povidone, hydroxyethyl cellulose,
polyoxyethylene, polyethylene glycol and mixtures thereof, preferably
hypromellose, povidone, copolymerized povidone, polyethylene glycol and
mixtures thereof. The proper solvent is selected from the group
consisting of ethanol, water, acetone, isopropyl alcohol or a mixture
thereof.

[0045] The thickness of the isolation layer can impact the release curve
of the pharmaceutical dosage form, and it may be controlled by coating
duration and amount. Based on the total weight of the double layered
tablet core, the weight gain of the isolation layer usually is no more
than 40 wt % of the tablet core. The thickness of the isolation layer
coating is usually between 0.05 and 3 mm.

[0046] In some embodiments, the isolation layer composition may further
comprise the pharmaceutically active ingredient, paliperidone. Based on
the total weight of the isolation layer composition, the pharmaceutically
active ingredient takes up 0 to 30 wt %, preferably 0 to 15 wt % in the
isolation layer. The release behavior, especially the -drug-release
behavior in the early release stage of the present dosage form, may be
adjusted by adjusting the content of the pharmaceutically active
ingredient in the isolation layer, which has been extensively
investigated through specific examples (FIG. 9 to FIG. 11).

[0047] The rigid membrane shell is the key point of the double layered
osmotic pump controlled release system, and it is the controlled release
layer in the present invention. The presence of a rigid membrane shell
may allow the penetration of outer liquids, such as water and biological
fluid, and prevent the penetration of the pharmaceutically active
ingredient, the osmotic agent and the permeable polymer. In the present
invention, after water penetrates the rigid membrane shell into the
tablet core such that the push layer is hydrated and swollen to promote
the hydrated drug layer suspension releasing from the release orifices on
the rigid membrane shell. The method for preparing the rigid membrane
shell is a common option for the skilled person in the art, and as an
example, it can be prepared by dissolving the controlled release layer
composition in a proper solvent to prepare a controlled release layer
coating solution and then spray the controlled release layer coating
solution on the tablet core using a high efficient coating pan and then
drying. The controlled release layer composition comprises a
semi-permeable controlled release membrane material, a plasticizer and a
porogen.

[0048] The semi-permeable controlled release membrane material is known
for the skilled person in the art, and is selected from the group
consisting of cellulose acetate, ethyl cellulose, acrylic resin and
mixtures thereof.

[0049] For adjusting the permeability of water through the rigid membrane
shell, a plasticizer and a porogen may be added. The porogen can improve
the permeability of water through the rigid membrane shell. Based on the
total weight of the controlled release layer composition, the amount of
the porogen is usually 0 to 50%, preferably 0 to 30%. The porogen may
include glycerin, povidone, copolymerized povidone, propylene glycol,
polyethylene glycol, water-soluble inorganic salts and mixtures thereof.

[0050] The plasticizer enables the membrane shell with more flexibility
and extensibility, and the use of the plasticizer can affect the release
rate of the drug. Based on the total weight of the controlled release
layer composition, the amount of the plasticizer is usually about 0 to
20%, preferably 0 to 15%. The plasticizer may be selected from the group
consisting of dimethyl phthalate, diethyl phthalate, dibutyl sebacate,
triethyl citrate, tributyl citrate, tributyl acetylcitrate, glycerol
acetate, castor oil and mixtures thereof.

[0051] The proper solvent for preparing the controlled release layer
coating solution according to the present invention is selected from the
group consisting of acetone, water, ethanol, isopropyl alcohol, methylene
chloride, methanol, ethyl acetate and mixtures thereof.

[0052] Additionally, an aesthetic coating layer may be coated on the
outside of the rigid membrane shell of the paliperidone double layered
osmotic pump controlled release tablet according to the present
invention, to provide additional functions, such as aesthetic appearance,
moisture-protecting, light-protecting etc., but have no influence on the
drug release of the paliperidone double layered osmotic pump controlled
release tablet according to the present invention. Based on the total
weight of the paliperidone double layered osmotic pump controlled release
tablet, the proportion of aesthetic coating layer is about 0 to 20%,
preferably 0.1 to 15%.

[0053] The aesthetic coating layer is made of an aesthetic coating layer
composition. The aesthetic coating layer composition comprises a coating
powder for forming the aesthetic coating, and, optionally, one or more
excipients selected from the group consisting of a colorant, a
plasticizer, an opacifying agent, an anti-sticking agent etc., and the
using amounts thereof are common selections for a skilled person in the
art. The coating powder for the aesthetic coating is the common option
for a skilled person in the art, and is selected from the group
consisting of commercially available Opadry and other coating powders
capable of forming the aesthetic coating. The opacifying agent may
include titanium dioxide, talc, silicon dioxide, and mixtures thereof.
The anti-sticking agent is mainly selected from the group consisting of
talc, magnesium stearate, glycerol monostearate and mixtures thereof.

[0062] The preparation method for the granules of the drug layer
composition is a common selection for a skilled person in the art, and
for example, it may be performed by dry granulation or wet granulation.
Since the one step granulation in a fluid bed is simple, quick and high
effective, it is preferably here to granulate by a wet granulation
process through a fluid bed. The materials for drug layer composition in
formulated amount are added into a fluid bed and uniformly mixed, sprayed
with 95% ethanol solution to prepare the drug layer composition granules
of the paliperidone double layered osmotic pump controlled release tablet
according to the present invention, dried completely and added with a
lubricant to be ready for use.

[0063] The preparation method for the push layer composition in the
present invention is similar to that for the drug layer composition, and
preferably, but not limited to, the fluid bed process. The materials for
the push layer composition in formulated amount are added into a fluid
bed and uniformly mixed, sprayed with a solvent to prepare granules of
the push layer composition of the paliperidone double layered osmotic
pump controlled release tablet according to the present invention, dried
completely and added with a lubricant to be ready for use.

[0064] The pressing method for the double-layered tablet core is a
conventional option for a skilled person in the art, and for example, may
be performed by a single punch tablet press or a double-layered tablet
press to produce the double-layered tablet core of the paliperidone
double layered osmotic pump controlled release tablet according to the
present invention. A proper amount of granules of the drug layer
composition is first added into a tablet slot to perform a pre-press, and
then the granules of the push layer composition are added to press into a
double-layered tablet core with appropriate hardness.

[0065] The method for coating an isolation layer and/or a controlled
release layer on the double-layered tablet core is a common option for a
skilled person in the art, and for example, it may be performed by
coating the prepared double-layered tablet core using a high efficient
coating pan. The coating solution of the isolation layer composition in
formulated amount is spray-coated on the tablet core to a predetermined
weight increment, and dried to remove the solvent to form an isolation
layer. After that, the controlled release coating is done.

[0066] The paliperidone double layered osmotic pump controlled release
tablet according to the present invention comprising at least one drug
release orifice. The drug release orifice can be prepared by mechanical
drilling or laser drilling. The geometry of the release orifice is not
limited, and may be any geometric shape, such as round, oval, square,
triangle etc., and the pore size is in a range of 0.3 to 1.2 mm.

[0067] FIG. 1 is a structure diagram of the paliperidone double layered
osmotic pump controlled release tablet according to an embodiment of the
present invention. As shown in FIG. 1, the rigid membrane shell 2
contains at least one drug release orifice 1; the push layer 5 is located
inside the rigid membrane shell and at the side away from the release
orifice 1; the drug layer is located inside the rigid membrane shell, and
at the side adjacent to the release orifice 1 and directly contacting
with the push layer 5; the isolation layer 3 is sandwiched between the
inside surface of the rigid membrane shell and the tablet core consisting
of the drug layer 4 and the push layer 5.

[0068] The step of coating an aesthetic coating layer is optional. In case
of no aesthetic layer in the paliperidone double layered osmotic pump
controlled release tablet according to the present invention, this step
is unnecessary. The coating method for the aesthetic layer is a common
option for a skilled person in the art. As an example, the materials for
the aesthetic layer composition may be dissolved in a proper solvent to
prepare an aesthetic layer coating solution, which is then coated on the
paliperidone double layered osmotic pump controlled release tablet
according to the present invention and dried to form the aesthetic layer.

[0069] The paliperidone double layered osmotic pump controlled release
tablet according to the present invention is a controlled release
preparation prepared by the osmotic pump preparation technique, and it
can release the drug under a predetermined release rate. After
administration, the drug release system will be activated through
absorbing moisture in the gastrointestinal tract, and the expansion
materials (high molecular compounds) of the push layer as the driving
part for drug release will absorb moisture to swell to push the hydrated
drug layer suspension out of the release orifice under a predetermined
release rate. The release rate is not impacted by gastrointestinal
peristalsis and pH value, the individual difference is small, the plasma
concentration is stable, and the therapeutic effectiveness is long, thus
eliminating the peak-trough phenomenon and fewer adverse reactions.

Beneficial Effects of the Invention

[0070] The beneficial effects of the present dosage form are based on the
advantages of the osmotic pump controlled release dosage form,
specifically embodied as followings.

[0071] (1) The dosage form according to the present invention has a unique
release behavior, that is, it shows an increasing drug release rate at
early release stage, and a constant release rate at the later release
stage. The designed drug release behavior can ensure the quick release of
the drug at early stage so as to achieve a rapid onset of the drug, and
at the same time, the later steady release rate can avoid the adverse
reaction (extrapyramidal symptoms) resulted from the fluctuation of
plasma concentration. The results of the in vivo pharmacokinetic
investigation show that the paliperidone double layered osmotic pump
controlled release tablet according to the present invention can quickly
onset, and maintain a relatively constant plasma concentration of the
active substance and a sustained therapeutic effectiveness of the active
substances, and therefore, the fluctuation in plasma concentration is
smaller and compliance is better.

[0072] (2) The impact of the factors such as the pH of the media, gastric
peristalsis and food is small, and the in vitro and in vivo relevance is
good.

[0073] (3) The phenomena of large fluctuation range in the plasma drug
concentration caused by common oral dosage form is avoided.

[0074] (4) The frequency of administration is reduced, and the safety,
efficacy and compliance of the administration are greatly improved.

[0075] (5) The present invention uses a double-layered osmotic pump
controlled release system. Compared with the commercially available
capsule-shaped controlled release tablets, the present invention greatly
simplifies the production process, and adopts the common production
equipments without any special equipment, and thus decreases production
cost greatly and is suitable for industrial production.

[0076] (6) The formulation of the tablet core has good thermal stability
and high glass transition temperature, and thus solving the problems in
drying process, sticking in the process of high-speed tablet-pressing and
the problems in the storage of the excipients and tablet, which are
resulted from using polyoxyethylene as an excipient for the tablet core.
The present invention provides a formulation which has a good
compressibility, smooth tablet surface and is suitable for high-speed
tablet-pressing, and adopts a mature and stable preparation technology,
and thus has a broader prospect for industrial production.

[0077] In the present invention, the terms of "rigid membrane shell",
"controlled release layer", "controlled release coating membrane" and
"controlled release coating" etc. present in different positions for
convenient description. The person skilled in the art should understand
that these different expressions have the same meaning.

BRIEF DESCRIPTION OF THE DRAWINGS

[0078] FIG. 1 is a schematic diagram showing the paliperidone
double-layered osmotic pump controlled release tablet according to one
embodiment of the present invention, wherein the said reference numbers
are:

[0094] FIG. 12 is a graph of the average release rate of the paliperidone
double-layered osmotic pump controlled release tablet according the
present invention prepared in Example 4;

[0095] FIG. 13 is a graph of the average release rate of the commercially
available capsule-shaped paliperidone osmotic pump controlled release
tablet (trade name: Invega, dosage: 6 mg) in the Comparative Example 1.

BEST MODE FOR CARRYING OUT THE INVENTION

EXAMPLES

[0096] Hereinafter, the present invention is further illustrated with the
following examples. Other purposes, advantages and novel features of the
present invention will be apparent for a skilled person in the art, or
will be comprehended through the practice of the present invention.

[0097] The following examples record generally the exemplary dosage form
and the method of preparing the osmotic pump dosage form. Unless
otherwise specified, all percentages are weight percentage. The following
examples are provided to facilitate the understanding of the invention,
but should not be understood as a limit for the scope of the invention.

[0098] The method of preparing the paliperidone double-layered osmotic
pump controlled release tablet is as follows:

[0099] The preparation of the drug layer: the drug layer composition
except for stearic acid were weighted according to the formulation of
Table 1 and then added into a fluidized bed after mixed uniformly, 95%
ethanol was sprayed onto granules till the particle size is appropriate.
After fully dried, the granules were passed through a 20-mesh sieve, and
then stearic acid was added therein, and mixed to be ready for use.

[0100] The preparation of the push layer: the push layer composition
except for stearic acid were weighted according to the formulation of
Table 1 and then added into a fluidized bed after mixed uniformly, 95%
ethanol was sprayed onto the granules till the particle size is
appropriate. After fully dried, the granules were passed through a
20-mesh sieve, and then stearic acid was added therein, and mixed to be
ready for use.

[0101] Press of the double-layered tablet core: the above prepared
granules of drug layer and push layer was pressed into double-layered
tablet core with proper hardness according to the formulation using a
double-layered tablet press machine. Firstly, 119 mg granules of the drug
layer composition were added into a tablet slot to perform pre-pressing,
and then about 90 mg granules of the push layer composition was added so
as to be pressed into the double-layered tablet core.

[0102] Coating of the isolation layer: a coating solution of the isolation
layer was prepared according to the above-mentioned formulation of Table
1. The above qualified double-layered tablet cores were put into a high
effective coating pan and then coated with the coating solution of the
isolation layer. The coated tablets were dried for 12 hours at 45°
C. to remove the residual organic solvent and water.

[0103] Coating of the controlled release layer: a coating solution of the
controlled release layer was prepared according to the above-mentioned
formulation of Table 1. The above double-layered tablet core with the
isolation layer were coated with the coating solution of the controlled
release layer. The coated tablets were dried for 12 hours at 45°
C. to remove the residual organic solvent and water.

[0104] The perforation of the coated tablet: a drug release orifice with a
diameter of 0.9 mm was made above the drug layer of the prepared tablet
by laser drilling so that the drug layer is connected with outside.

[0105] Coating of the aesthetic coating layer: Opadry coating powder was
dissolved in water to prepare the coating solution for aesthetic coating.
Then the perforated controlled release tablet was coated with the coating
solution. The coated tablets were dried for 12 hours at 45° C. to
obtain the final product.

Example 2

[0106] Paliperidone double-layered osmotic pump controlled release tablet
was prepared according to the formulation of Table 1 in the manner
described in Example 1, except that 139 mg granules of the drug layer
composition were used during the pressing of the double-layered tablet
core.

Example 3

[0107] Paliperidone double-layered osmotic pump controlled release tablet
was prepared according to the formulation of Table 1 in the manner
described in Example 1, except that 138 mg granules of the drug layer
composition were used during the pressing of the double-layered tablet
core.

Examples 4˜7

[0108] Paliperidone double-layered osmotic pump controlled release tablet
was prepared according to the formulation of Table 1 in the manner
described in Example 1, except that 100 mg granules of the drug layer
composition were used during the pressing of the double-layered tablet
core.

Example 8

[0109] Paliperidone double-layered osmotic pump controlled release tablet
was prepared according to the formulation of Table 1 in the manner
described in Example 4, except that the step of coating the aesthetic
coating layer was not performed.

Experimental Example

[0110] Release Determination

[0111] According to the method of Release Test (method I of Appendix XD,
Part II, Chinese Pharmacopeia 2005), a device for Dissolution Test
(method II of Appendix XD, Part II, Chinese Pharmacopeia 2005) was used
to measure the drug release characteristics of the paliperidone
double-layered osmotic pump controlled release tablet prepared according
to the present invention, the specific steps are as follows.

[0112] (1) The paliperidone double-layered osmotic pump controlled release
tablet according to the present invention was put into a small metal
basket, followed by addition of 500 ml of a media (a solution of
hydrochloric acid with 0.2% sodium chloride), and the rotating speed was
75 rpm. In accordance with the above method, 5 ml of solution was sampled
every 2 hours in 24 hours and then centrifuged (8000 rpm, 15 min);
meanwhile the media with the same temperature and volume was
supplemented. The supernatant fluid was collected as the test solution.

[0113] (2) 12 mg paliperidone as control was weighted and added into a
volumetric flask of 100 ml, followed by addition of methanol for
dissolving and setting volume, and then the resulted solution was shaken
up to obtain a uniform mixture. 5 ml of the solution was taken
accurately, added into a volumetric flask of 100 ml, followed by addition
of a solution of 0.2% sodium chloride in hydrochloric acid for setting
volume, and then the resulted solution after being shaken up was used as
the control solution.

[0114] (3) The drug release at each time point was measured through a high
performance liquid chromatography by isocratic elution with an octadecyl
silane-bonded silica gel as the filler and methanol-ammonium formate
buffer solution (35:65) as the mobile phase under a detection wavelength
of 279 nm. 20 μl of each of the above-mentioned control and the test
solutions was taken accurately and then injected into the liquid
chromatograph. Next, peak area was recorded, and cumulative release
amounts of each tablet at different times were calculated by using the
peak area in accordance with the external reference method.

Experimental Example 1

Release Rate in Different Media

[0115] Release rate was determined in four media simulating the
gastrointestinal tract circumstance at different pH values, i.e., water,
pH6.8, pH4.5 and pH1.2, so as to evaluate the influence of media on the
release characteristics of the paliperidone double-layered osmotic pump
controlled release tablet according to the present invention prepared in
Example 4. The results were showed in FIG. 2.

[0116] Meanwhile, simulated intestinal fluid having the formulations
showing in the following Table 2 were used to further investigate the
food effect on the release characteristics of the paliperidone
double-layered osmotic pump controlled release tablet according to the
present invention prepared in Example 4, i.e., the release
characteristics under the state of fasting and fed. The results were
showed in FIG. 3.

[0117] As can be seen from FIG. 2, the paliperidone double-layered osmotic
pump controlled release tablet according to the present invention
released drugs at a predetermined rate in the four different media at
different pH values, that is to say, the media has little effect on the
release characteristics.

[0118] As can be seen from FIG. 3, the drug release does not have
significant difference between fasting and fed in the simulated
intestinal fluid. The results of the pharmacokinetic study of the
paliperidone double-layered osmotic pump controlled release tablet
according to the present invention in Beagle dogs coincide with the
results of the release curve in vitro. Therefore, it can be foreseen that
the paliperidone double-layered osmotic pump controlled release tablet
could release drug uniformly when used in clinic, so as to provide more
smooth and persistent therapeutic efficacy for patients.

Experimental Example 2˜9 and Comparative Example 1

[0119] A solution of 0.2% sodium chloride in hydrochloric acid (29.7 ml of
concentrated hydrochloric acid was diluted with water to 4000 ml) was
used as the media to determine the release characteristics of the
paliperidone double-layered osmotic pump controlled release tablets
prepared in Examples 1˜8 according to the present invention and the
commercially available capsule-shaped paliperidone osmotic pump
controlled release tablet (trade name: Invega, dosage: 6 mg)
respectively. The results are showed in FIGS. 4˜13 respectively.

[0120] FIGS. 4˜11 illustrated the release curves of the paliperidone
double-layered osmotic pump controlled release tablets according to the
present invention prepared in Examples 1˜8 respectively. As can be
seen in FIGS. 4˜11, the paliperidone double-layered osmotic pump
controlled release tablets according to the present invention can realize
the regulation of drug release rate in a certain range, and each of the
said controlled release tablets (Examples 1˜8) shows a gradually
increasing the drug release rate at the early stage, and after a certain
time, releases the drug constantly at a predetermined rate, so as to
achieve the predetermined drug release mode of "increasing first and then
being constant". Thus it will ensure that the paliperidone double-layered
osmotic pump controlled release tablet of the present invention can
achieve rapidly a blood concentration that is effective for treatment at
the early stage of drug release, and then release drug at a steady and
constant speed at the later stage of drug release, thereby maintaining a
more smooth curve of blood concentration, decreasing the fluctuation of
blood concentration, reducing the adverse reactions (mainly
extrapyramidal symptoms) of nervous system of atypical antischizophrenic
drugs, and improving the safety, efficacy and compliance of
administration significantly.

[0121] FIGS. 12˜13 show the average release rates of the
paliperidone double-layered osmotic pump controlled release tablet
prepared in Example 4 according the present invention and the
commercially available capsule-shaped paliperidone osmotic pump
controlled release tablet respectively. It can be seen from the
comparison of FIG. 12 and FIG. 13 that the paliperidone double-layered
osmotic pump controlled release tablet according the present invention
has a more steady average release rate compared with the commercially
available capsule-shaped paliperidone osmotic pump controlled release
tablet, and thereby it is better for decreasing the fluctuation of blood
concentration and reducing the occurrence of the adverse reactions of the
drug.

INDUSTRIAL APPLICABILITY

[0122] The present invention adopts the double-layered osmotic pump
controlled release system such that not only the production process steps
is simplified, the workload during preparing process is reduced, and the
production cycle period is shortened, but also the production equipments
used is common without requirement of any special equipment, the
operation is simple, thereby decreasing the investment cost at the
initial stage of production process and being suitable for industrial
production.

[0123] In addition, the selected novel excipient for the tablet core have
good thermal stability, high glass transition temperature and good oral
safety, so as to solve the problem resulting from using polyoxyethylene
as the main excipient of the tablet core. The formulation provided by the
present invention has good compressibility and is suitable for high speed
tablet-pressing,

[0124] and the pressed tablet core has a smooth surface with good
hardness. Furthermore, the excipient of the present dosage form has a
lower cost, and thus can reduce the production cost significantly. In
addition, the process for the present dosage form is mature and steady,
and has [0125] a broader industrial prospect for industrial production.